1. Field of the Invention
The present invention relates generally to the fields of oncology, molecular biology, cell biology, and cancer. More particularly, it concerns cancer diagnosis, prognosis or classification using molecular markers.
2. Description of Related Art
Colorectal cancer (CRC) is one of the most common malignancies worldwide, and is a major cause of cancer-related deaths (Siegel 2012). Survival rates of patients with CRC have increased in the past few years, possibly as a result of earlier diagnosis and improved treatment regimens, nonetheless, approximately 30-50% of patients who undergo curative resection subsequently experience local tumor recurrence or metastasis (Lieberman 2012). This subgroup of patients usually receive chemotherapy often in combination with monoclonal antibody therapy, with a median overall survival duration of ˜20 months, and the response rates at best around 50% (Halama 2008). However, the substantial financial costs associated with CRC treatment not only present an economic burden, but treatment of all patients with chemotherapy without a priori selection leads to overtreatment of patients with toxic agents that produce severe adverse effects (Meropol 2007). In order to overcome this clinical challenge, there is a clear need to identify biomarkers that will facilitate the identification of patients with a poor prognosis, and permit personalized treatment strategies for patients with high risk of CRC recurrence.
Blood-based tumor markers are gaining acceptance as a potential alternative for noninvasive detection of cancer. Serum carcinoembryonic antigen (CEA) is one marker that is frequently used for predicting prognosis in patients with CRC (Duffy 2007; Reiter 2000). Unfortunately, CEA levels do not always correlate with the presence of metastasis, and the incidence of false-positive and false-negative results are very high (Fakih 2006; Tan 2009). Consequently, there is a dire need to identify highly robust biomarkers that can clinically determine cancer prognosis, and are better indicators of patient outcome than the existing TNM staging system or other conventional tumor markers of CRC (Duffy 2001).
MicroRNAs (miRNAs) are non-coding RNA molecules of approximately 21-23 nucleotides in length that regulate target gene expression by interfering with their transcription or by inhibiting translation (Cortez 2009). miRNAs play crucial roles in diverse cellular biological processes, including differentiation, proliferation, growth, migration and survival. The discovery that miRNA expression is frequently dysregulated in malignant tumors underpins their critical role, which is a matter of active investigation, both from a basic science perspective and for its clinical usefulness (van Kouwenhove 2011). Recently, several studies have highlighted the diagnostic and prognostic utility of plasma and serum-based miRNA levels, because tumor-derived miRNAs are present in human circulation in remarkably stable forms that are protected from endogenous ribonuclease activity (Mitchell 2008). These reports suggest that plasma/serum miRNA-based assays may constitute accurate methods for diagnosis and prognosis of human cancer, although to date only a few studies have specifically addressed the clinical significance of circulating miRNAs in patients with CRC (Ng 2009; Huang 2010; Wang 2012; Pu 2010; Cheng 2011).
Distant metastasis is the major cause of serious morbidity and mortality in cancer patients. Liver metastasis is the most common manifestation, and occurs in >50% of CRC patients with metastases.2 Aggressive liver resection in metastatic CRC patients may improve the 5-year survival, but most of these patients still experience tumor recurrence (Rees 2008; Fernandez 2004). Although current diagnostic imaging tools such as contrast enhanced computed tomography (CT), positron emission tomography-CT (PET-CT), and magnetic resonance imaging (MRI) can facilitate the detection of CRC metastasis (Bipat 2007), these modalities are of limited value because of the inability to identify truly early metastatic lesions and the costs associated with advanced imaging. In view of this clinical challenge, there is a clear need for the development of metastasis-specific molecular biomarkers that can help predict outcomes and direct more effective therapies.
However, despite many attempts to establish prognostic, diagnostic or metastatic markers to understand the clinical biology of patients with colorectal cancer, validated clinical or biomarker parameters are lacking in many aspects. Therefore, there remains a need to discover novel prognostic, diagnostic or metastatic markers for cancer patients, especially colorectal cancer patients.